While the progress in identifying major cancer susceptibility genes has been gratifying, our ability to intervene at the molecular level in order to reduce the risk associated with mutations in these genes is embryonic. We are in urgent need of safe and effective strategies through which the risk of cancer in mutation carriers can be reduced now. Strategic planning within DCEG is now underway to create a sound plan under which the Division can assume a larger role in intervention studies of this type. (a) Concurrent with this process, we have initiated efforts to support the breast cancer and colon cancer chemoprevention trials currently underway within NCI's Division of Clinical Sciences by urging members of our cancer-prone families to participate in these important studies, and coordinating referrals for those who are interested. Trials currently accruing patients include a Phase II breast cancer prevention trial [open to women at increased risk of breast cancer] utilizing the selective estrogen receptor modulator raloxifene, and a Phase II colon cancer trial [targeting members of hereditary nonpolyposis colorectal cancer syndrome families] employing the selective COX-2 inhibitor, celecoxib.(b) Also under discussion is the possibility of initiating a series of Phase II clinical trials (in collaboration with the University of Arizona Cancer Center) among patients with dysplastic nevi, a known melanoma precursor, to seek biologically active compounds which might hold promise as topical skin cancer chemoprevention agents. These studies have evolved from the Arizona Cancer Center's Skin Cancer Chemoprevention Program Project Grant. Candidate agents which would be studied include topical tretinoin (all-trans retinoic acid), 9-cis retinoic acid, diflouromethylornithine (DFMO), epigallotcatechin gallate, perillyl alcohol and sodium salicylate. A panel of surrogate endpoint biomarkers would be employed as indicators of biological activity. This project would represent a natural evolution of DCEG's long-standing interests in hereditary melanoma and melanoma precursors.(c) Another project currently under consideration is a combined dietary/medication intervention trial among persons with Familial Adenomatous Polyposis. This would be a collaborative undertaking with the Nutrition Epidemiology Branch, and would build upon recent evidence suggesting that the selective COX-2 inhibitor, celecoxib, is active in reducing the number and size of polyps in patients with FAP. The study contemplated would permit assessment of gene-environment interactions in the polyp prevention pathway. (d) A study of the prevalence of BRCA1/2 founder mutations is now underway in a series of 1000 Ashkenazi Israelis with prostate cancer during 1994 - 1995. The genetic testing on these samples is expected to be completed before the end of the year. In collaboration with the Laboratory of Pathology/DCS, a systematic comparison of the histopathology of BRCA1/2 mutation associated prostate cancers with that of cancers not associated with such mutations is planned. We also will perform loss of heterozygosity studies on BRCA1,2-associated prostate cancers. The goal of this study is to resolve the current uncertainty regarding whether prostate cancer is one of the features of the BRCA1,2 syndromes. If the answer proves to be yes, this will provide the rationale for proceeding with a study of prostate cancer screening and prevention among the men from our HBOC families who are mutation carriers. This would entail a collaboration with investigators from the Urological Oncology Branch/Division of Clinical Sciences.(e) An issue yet to be resolved is the role that CGB might play in the planning, conduct and analysis of national, multi-institutional Phase III intervention trials which target genetically high-risk populations, perhaps in collaboration with such organizations as the Cancer Genetics Network, the Cooperative Family Registries for Breast, Colon Cancer, the Early Detection Resource Network, site-specific SPORES, etc. This issue is most likely to require formal consideration with regard to the possibility of mounting a Phase III randomized chemoprevention trial for women who are carriers of mutations in the BRCA1/2 genes. At present, there is no single organization in the United States with all of the capabilities required to undertake such a study. The clinical trials cooperative groups have expertise, resources and infrastructure relative to the conduct of large randomized studies, but historically have not had access to genetically high-risk populations. Similarly, CGN and CFR have access to the right kind of study subjects, but no experience in the conduct of clinical trials. The Clinical Genetics Branch may be optimally positioned to play a central role in such studies.